Dr. Roopam Jain, Professor & Head, Dept. of Pathology & Blood Bank

1. Dr. Roopam Jain,
Professor & Head,
Dept. of Pathology & Blood Bank

3. INDEX
 Introduction
 Phases
 Control Of Cell Growth And Differentiation
The Proliferative Potential Of Different CellTypes
Checkpoints
Regulation Of Eukaryotic CellCycle

4. • The sequence of events that results in cell
division is called the cell cycle.
The sequence of events that results in cell
division is called the cell cycle.

5. • The cell cycle, or cell-division cycle, is the series of events
that take place in a cell leading to duplication of its DNA
(DNAreplication) and division of cytoplasm and organelles
to produce two daughter cells.
• The cell-division cycle is a vital process by which a single-
celled fertilized egg develops into a mature organism, as well
as the process by which hair, skin, blood cells, and some
internal organs are renewed.
• Most cancers are in essence caused by deregulation of the
cell cycle, and many oncogenes and tumor suppressor
genes are intrinsic components of the cell cycle or can
influence its progression.

6. • In bacteria, which lack a cell nucleus, as in prokaryotes, the cell cycle
extends from the end of cell division to the beginning of DNA
replication and then the splitting of the bacterial cell into two daughter
cells.
• In cells with a nucleus, as in eukaryotes, the cell cycle is also divided
into two main stages:
During interphase, the cell grows, accumulating nutrients needed for
mitosis, and undergoes DNA replication preparing it for celldivision.
During the mitotic phase (including mitosis and cytokinesis),the
replicated chromosomes and cytoplasm separate into two new
daughter cells.
• To ensure the proper division of the cell, there are control mechanisms
known as cell cycle checkpoints.

8. • The eukaryotic cell cycle consists of four distinct phases:
G0 Phase- Quiescent cells that are not actively cycling
Interphase
o G1 Phase(presynthetic growth)
o S Phase (DNA synthesis)
o G2 Phase(premitotic growth)
M Phase
Mitotic phases
o Prophase
o Metaphase
o Anaphase
o Telophase
Cytokinesis Phase

10. • Cells can enter G1 either from the G0 quiescent
cell pool, or after completing a round of
mitosis, as for continuously replicating cells.
• Each stage requires completion of the
previous step, as well as activation of necessary
factors ;
• nonfidelity of DNA replication, or cofactor
deficiency result in arrest at the various
transition points.

11. OVERVIEW OF THE CELLCYCLE

12. INTERPHASE
• Interphase includes:
•G1 Phase:
•S Phase:
•G2 Phase:

13. INTERPHASE: G1 PHASE
• Recovery from previous
division
• Cell doubles its organelles
• Cell grows in size
• Accumulates raw
materials for DNA
synthesis
(DNA replication)

14. INTERPHASE: S PHASE
• DNA replication
• Proteins associated with
DNA, are synthesized

15. INTERPHASE: G2 PHASE
• Between DNA
replication and onset of
mitosis
• Cell synthesizes
proteins necessary
for division

16. CELL CYCLE: MITOSISPHASE
Mitosis phase includes:
• Mitosis (karyokinesis)
• Nuclear division
• Daughter chromosomes
distributed to two daughter
nuclei
• Cytokinesis
• Cytoplasm division
• Results in two genetically
identical daughter cells

17. MITOSISPHASE: PROPHASE

18. MITOSIS PHASE: PROPHASE
What’s happening? What the cell looks like?
• Chromatin condenses.
• Centrosomes separate,
moving to opposite ends of
the nucleus
• The centrosomes start to form
a framework used to separate
the two sister chromatids
called the mitotic spindle, that
is made of microtubules
• Nucleolus disappears
• Nuclear envelope
disintegrates

20. MITOSIS PHASE: PROMETAPHASE
What’s happening? What the cell looks like?
• Nuclear envelope
fragments
• Chromosomes become
more condensed
• A kinetochore is formed
at the centromere, the
point where the sister
chromatids are attached
• Microtubules attach at
the kinetochores

21. MITOSIS PHASE: METAPHASE
What’s happening? What the cell looks like?
• Chromosomes align on an
axis called the metaphase
plate
• Note: the spindle
consists of
microtubules, one
attached to each
chromosome

23. MITOSIS PHASE: ANAPHASE
What’s happening? What the cell looks like?
• Each centromere splits
making two chromatids
free
• Each chromatid moves
toward a pole
• Cell begins to elongate,
caused by microtubules
not associated with the
kinetochore

25. MITOSIS PHASE: TELOPHASE
What’s happening? What the cell looks like?
• Formation of nuclear
membrane and nucleolus
• Short and thick chromosomes
begin to elongate to form long
and thin chromatin
• Formation of the cleavage
furrow - a shallow groove in the
cell near the old metaphase plate
• Cytokinesis = division of the
cytoplasm

27. • Mitosis is immediately followed by cytokinesis, which
divides the nuclei, cytoplasm, organelles and cell
membrane into two cells containing roughly equal shares of
these cellular components.
• Mitosis and cytokinesis together define the division of the
mother cell into two daughter cells, genetically identical to
each other and to their parent cell.
• This accounts for approximately 10% of the cell cycle.
CYTOKINESIS PHASE

31. RESULTS OF MITOSIS
• Two daughter nuclei
• Each with same
chromosome number as
parent cell ( 2n)
• Genetically identical to
each other and the
parent cell

32. SIGNIFICANCE OF MITOSIS
• Permits growth and repair.
• In plants it retains the ability to
divide throughout the life of the
plant
• In mammals, mitosis is necessary:
• Fertilized egg becomes an
embryo
• Embryo becomes a fetus
• Allows a cut to heal or a broken
bone to mend

33. CONTROL OF CELL GROWTH
AND DIFFERENTIATION

34. • Entry of new cells into a tissue population is largely
determined by their proliferation rate, while cells can
leave the population either by cell death or
differentiation into another cell type.
• Cell proliferation can be stimulated by intrinsic growth
factor, injury, cell death, or even mechanical deformation
of tissues.
• The biochemical mediators and /or mechanical stressors
present in the local micro-environment can either
stimulate or inhibit cell growth. The excess or deficiency
of these can result in net cell growth.
• Although growth can be accomplished by shortening the
length of the cell cycle or decreasing the rate of cell loss.

36. • Mechanisms regulating cell populations.
• Cell numbers can be altered by
increased or decreased rates of stem
cell input, cell death due to
apoptosis, or changes in the rates
of proliferation or differentiation.

37. THE PROLIFERATIVE
POTENTIAL OF DIFFERENT
CELL TYPES

38. • The cells of the body are divided into three groups on the basis of their
regenerative capacity and their relationship to the cell cycle:
 Labile cells - Cells of these tissues are continuously being lost and
replaced by maturation from stem cells and by proliferation of mature
cells.
 E.g.- epidermis and GI Tract.
 Stable cells - Cells of these tissues are quiescent and have
only minimal replicative activity in their normal state.
 E.g.- hepatocytes.
 Permanent cells - Cells of these tissues are considered to be
terminally differentiated and non-proliferative in postnatal life.

40. CHECKPOINTS

41. To ensure the proper division of the cell,
there are control mechanisms known as
cell cycle checkpoints

42. • Cell cycle checkpoints consist of a network of regulatory
proteins that monitor and dictate the progression of the
cell through the different stages of the cell cycle.
• Checkpoints prevent cell cycle progression at specific
points, allowing verification of necessary phase
processes and repair of DNA damage.
• The cell cannot proceed to the next phase
until checkpoint requirements have been
met.
• There are several checkpoints to ensure that damaged
or incomplete DNA is not passed on to daughter cells.

44. 1. The G1/S checkpoint:- G1/S transition is a rate-limiting step in
the cell cycle and is also known as restriction point. This is
where the cell checks whether it has enough raw materials to
fully replicate its DNA. An unhealthy or malnourished cell will
get stuck at this checkpoint.

45. 2. The G2/M checkpoint:- G2/M checkpoint is where the
cell ensures that it has enough cytoplasm and
phospholipids for two daughter cells. It also checks to
see if it is the right time to replicate.

46. Later in the cell cycle, the G2-M restriction
point ensures that there has been accurate
genetic replication before the cell actually
divides.

47. 3. The metaphase (mitotic) checkpoint:- In this checkpoint,
the cell checks to ensure that the spindle has formed
and that all of the chromosomes are aligned at the
spindle equator before anaphase begins.

48. When cells do detect DNA irregularities, checkpoint
activation delays cell cycle progression and triggers
DNA repair mechanisms.
If the genetic derangement is too severe to be
repaired, the cells will undergo apoptosis;
alternatively, they may enter a nonreplicative state
called senescence—primarily through p53-dependent
mechanisms.

49. REGULATION OF
EUKARYOTIC CELL CYCLE

50. • The cell cycle is regulated by activators and
inhibitors.
• Cell cycle progression is driven by proteins
called cyclins— named for the cyclic nature
of their production and degradation—and
cyclin-associated enzymes called cyclin-
dependent kinases (CDKs).

51. • CDKs acquire the ability to phosphorylate
protein substrates (i.e., kinase activity) by
forming complexes with the relevant cyclins.
• Transiently increased synthesis of a particular
cyclin leads to increased kinase activity of the
appropriate CDK binding partner; as the CDK
completes its round of phosphorylation, the
associated cyclin is degraded and the CDK activity
abates.
• Thus, as cyclin levels rise and fall, the activity
of associated CDKs likewise wax and wane.

53. • More than 15 cyclins have been identified;
cyclins D, E, A, and B appear sequentially
during the cell cycle and bind to one or more
CDKs.
• The cell cycle can thus be conceived as a relay
race in which each leg is regulated by a
distinct set of cyclins: as one collection of
cyclins leaves the track, the next set takes
over.

54. • Enforcing the cell cycle checkpoints is the job
of CDK inhibitors (CDKIs); they accomplish this
by modulating CDK-cyclin complex activity.
• There are several different CDKIs:
• One family—composed of three proteins called
p21 (CDKN1A), p27 (CDKN1B), and p57
(CDKN1C)— broadly inhibits multiple CDKs.
• The other family of CDKI proteins has selective
effects on cyclin CDK4 and cyclin CDK6; these
proteins are called p15(CDKN2B), p16(CDKN2A),
p18(CDKN2C), and p19(CDKN2D).

56. • Role of cyclins, cyclin-dependent kinases (CDKs), and
CDK inhibitors in regulating the cell cycle.
• The shaded arrows represent the phases of the cell
cycle during which specific cyclin-CDK complexes are
active.
• Cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2
regulate the G1-to-S transition by phosphorylating the
Rb protein (pRb). Cyclin A-CDK2 and cyclin A-CDK1
are active in the S phase.
• Cyclin B-CDK1 is essential for the G2-to-M transition.
• Two families of CDK inhibitors can block activity of
CDKs and progression through the cell cycle.
• The so-called INK4 inhibitors, composed of p16, p15,
p18, and p19, act on cyclin D-CDK4 and cyclin D-
CDK6. The other family of three inhibitors, p21, p27,
and p57, can inhibit all CDKs.

57. • Defective CDKI checkpoint proteins allow
cells with damaged DNA to divide, resulting
in mutated daughter cells with the
potential of developing into malignant
tumors.